Many chemical compounds are substantially insoluble in water. There are several different approaches to solve the solubility problem of poorly water-soluble chemical compounds. These include traditional solubilizing approaches using a combination of solvents, surfactants and co-solvents, various dispersion techniques, as well as micronization, complexation and liposomal delivery techniques.
Dissolution of active agents in solvents is an approach which is used both for delivery of pesticides into plant crops and for preparation of water-immiscible drugs for in vivo delivery. This approach becomes problematic for pesticides which, unlike pharmaceutical agents used in low concentrations, require relatively high concentrations of active agent for pest control, and accordingly large amounts of solvents for dissolution. Typically, the solvents used are not environmentally acceptable and pose potential health and safety risks to handlers. Further, the handler is exposed to toxic and/or irritant levels of pesticides while manipulating the materials during the dissolution. Hence, some current methods of agrochemical formulation and delivery are disadvantageous, as they are environmentally “unfriendly” and expose handlers to excessive levels of pesticides and solvents.
Current technology for delivering insoluble agents (as described in, e.g., U.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442) involves either coating small active agent particles with surface active substances or dissolving the drug in a suitable lipophilic carrier and forming a stabilized emulsion. For many of these processes, emulsions are the starting point employed to achieve small particle size of poorly water-soluble agents using a hydrophobic solvent (e.g., oil) and a stabilized mechanism within an aqueous medium. One of the problems of these formulations is that certain particles in suspension tend to grow over time because of the “Oswald ripening” phenomenon. Another problem is that many insoluble agents of interest do not show appreciable solubility within traditional oil emulsion systems. One reason for this is that solubility is not strictly defined by polarity, but also includes hydrogen bonding, dipole-dipole interactions, ionic stabilization and atom-to-atom interactions.
Another approach directed to delivery and release of poorly soluble chemical compounds includes their formulation as nano-sized particles (nanoparticles). Nanoparticles of organic compounds can be produced through the use of microemulsions, comprising either water-in-oil “reverse” microemulsions, or oil-in-water microemulsions. Nanoparticles prepared from water-in-oil microemulsions have been disclosed with respect to each of cholesterol, Rhovanil and Rhodiarome (Debuigne et al. Langmuir 2000, 16(20), 7605-7611), and nimesulide (Debuigne et al. J. Pharm Belg. 2000 55(2), 59-60).
Nanoparticles prepared by methods comprising solvent diffusion (not solvent evaporation) from oil-in-water microemulsions have been disclosed with respect to griseofulvin, an antifungal drug (Trotta M., et al. Int. J. Pharm. 2003, 245, 235-242). Latex nanoparticles can also be obtained by polymerization (not solvent evaporation) in oil-in-water microemulsion (Ozer et al. J. App. Poly. Sci. 2000, 78(3), 569-575). Solid lipid microspheres can be prepared by solidification (not solvent evaporation) from oil-in-water microemulsion (U.S. Pat. No. 5,250,236). Pigment nanoparticles can be produced from oil-in-water microemulsion in ink-jet printing processes by evaporation of volatile solvent on a substrate surface (Magdassi and Ben Moshe Langmuir 2003, 19(3), 939-942).
Nanoparticles obtained using emulsion (not microemulsion) and solvent evaporation techniques have been disclosed with respect to cellulose derivatives and polylactic acid (Desgouilles et al. Langmuir 2003, 19, 9504-9510); and pilocarpine encapsulated within poly(lactide-co-glycolide) polymer (Yoncheva et al. J. Microencapsul. 2003, 20(4), 449-458).
WO 2005/072709 discloses a drug delivery system comprising nanoparticles of a water poorly soluble drug dispersed in a polymeric hydrophilic bead, and a method for producing the drug delivery system. The disclosed method comprises mixing an oil-in-water submicron emulsion comprising a poorly water soluble drug, with a water-soluble bead forming polymer; providing conditions enabling bead formation; optionally evaporating volatile organic solvent and water used in earlier steps, and thereby obtaining dry beads containing dispersed nanoparticles of the poorly water soluble drug.
WO 2005/102507 describes a process for preparing nanoparticles from oil-in-water nanoemulsions, in which the nanoemulsion is prepared by phase inversion, or temperature inversion techniques.
WO 2005/020933 relates to a process for the preparation of polymeric nanoparticles with target molecules bonded to the surface of the particles and having sizes of up to 1000 nm, preferably 1 nm to 400 nm, more preferably 1 nm to 200 nm that are dispersed homogeneously in aqueous solution. The polymeric nanoparticles are prepared using emulsion polymerization technique.
WO 01/88046 describes a process to pattern organic nanoparticles by ink-jet printing of microemulsions.
U.S. Pat. No. 5,091,188 discloses injectable formulations of water-insoluble drugs as aqueous suspensions of phospholipid-coated microcrystals, wherein the drug is reduced to 50 nm to 10 μm dimensions by sonication or other high shear processes in the presence of phospholipid or another membrane-forming amphipathic lipid.
U.S. Pat. No. 4,725,442 discloses preparation by sonication of microdroplets of water-insoluble drugs coated with phospholipids, wherein the microdroplets are from about 200 Angstroms up to one micron in diameter.
U.S. Pat. No. 5,879,715 relates to a process for the production of inorganic nanoparticles by precipitating the inorganic nanoparticles by a precipitating agent from a microemulsion with a continuous and a non-continuous phase and concentrating the precipitated nanoparticles employing an ultra filtration membrane.
U.S. Pat. No. 5,874,029 describes the production of microparticles and nanoparticles in which a compressed fluid and a solution including a solvent and a solute are introduced into a nozzle to produce a mixture. The mixture is then passed out of the nozzle to produce a spray of atomized droplets. The atomized droplets are contacted with a supercritical antisolvent to cause depletion of the solvent in the droplets so that the particles are produced from the solute. Preferably, these particles have an average diameter of 0.6 μm or less. This process relies on a spraying type vaporization process.
US Patent Application No. 2005/0170004 relates to nanoparticles comprising an organic wax and a surfactant, wherein a peptide, polysaccharide or glycoprotein is electrostatically attached to the nanoparticle. Hsu et al. (AAPS Pharm Sci Tech 2003, 4(3), E32) relates to nanoparticles of encapsulated coenzyme Q10 in lyophilized and aqueous suspension forms, and their production from microemulsions.
Preparation of Water-Redispersible Powders and Water-Wettable Polymeric Powders has also been disclosed. U.S. Pat. Nos. 5,472,706 and 5,750,142 disclose a lyophilized composition comprising submicron particles and an amino compound cryoprotectant, and a method of making a lyophilized composition, wherein the method involves use of a submicron oil-in-water emulsion comprising an amino compound cryoprotectant. European Patent No. 211257 relates to lyophilized emulsion compositions comprising carbohydrates which are intended for parenteral administration of hydrophobic drugs.
U.S. Pat. No. 6,835,396 discloses a process for preparing submicron sized particles of a pharmacologically active compound by forming a crude dispersion in a water immiscible solvent and a surfactant, subjecting the crude dispersion to sonication in order to form a fine dispersion, freezing the fine dispersion, and lyophilizing the frozen dispersion to obtain particles having a diameter less than 500 nm.
U.S. Pat. No. 6,872,773 discloses preparation of a powder by spray-drying of an aqueous dispersion of polymer particles. U.S. Pat. No. 6,841,613 discloses water re-dispersible granules obtainable by drying an emulsion obtained by polymerizing. Other powder forming processes comprise a polymerization step, such as disclosed for example in U.S. Pat. No. 6,841,595 relating to the preparation of protective colloid-stabilized, emulsifier-free, aqueous dispersions based on at least two monomers, and U.S. Pat. No. 6,770,722 relating to the preparation of protective-colloid-stabilized polymers by continuous emulsion polymerization.
As outlined above, prior art nanoparticle formulations intended for delivery of water-insoluble organic compounds comprise encapsulating materials and/or special ingredients and techniques required for maintaining the final material in powder or dispersed form. Such formulations and methods suffer from increased production time and costs, and more complicated regulatory approval processes.
U.S. Patent Application No. 2006/0063676 relates to a transparent stable aqueous oil-in-water microemulsion of an agrochemical and a surface active agent as emulsifier, wherein 50% of the droplets of the microemulsion have a size in the range from 100 to 300 nm.
Dowler et al. (J. Agric. Food Chem. 1999, 47, 2908-2913) relate to use of emulsification using the solvent dichlomethane and the polymer ethyl cellulose for the preparation of microcapsules for preparation of controlled release formulations of the herbicides alachlor and metolachlor. The solvent was removed by allowing it to evaporate at room atmosphere. Perez-Martinez et al. (Pest Manag Sci 2001, 57:688-694) disclose the same method for preparation of controlled release microcapsules of the pesticide norfluazon.
There remains an unmet need for nanoparticle formulations of water-insoluble pesticides compounds which can be produced by simple and cost-effective techniques.